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    临床研究

  • XIE Jing-yuan;ZHU Ping;SHEN Ping-yan;REN Hong;HUANG Xiao-min;LI Xiao;CHEN Xiao-nong;CHEN Nan
    2008, 24(10): 685-689.
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    Objective To compare the efficacy between the two-cuff swan neck catheter and the Tenckhoff catheter in continuous ambulatory peritoneal dialysis (CAPD) patients prospectively. Methods One hundred and ten patients with end-stage renal disease (ESRD) were selected as candidates, who received catheter implantation and CAPD therapy for the first time. Patients were divided into group A (swan neck catheter group) and group B (Tenckhoff catheter group), 55 patients for each group. Catheters of both groups had a straight end and were implanted by routine surgical procedure. One-year follow-up was performed and information was recorded such as complications, survival time, quit of dialysis, death, etc. Survival analysis was carried out by Kaplan-Meier method and Log-Rank tests. Results At the end of follow-up, 17 patients died, 3 received renal transplantation, 8 were transferred to hemodialysis, 3 went to other hospitals, and 79 patients (71.8%) remained in our department for CAPD. Twenty-six patients of both groups had peritonitis with a total of 35 occurrences. The total incidence of peritonitis was 0.32 times/patient year, with the detailed figure of 0.35 times/patient year for group A and 0.29 times/patient year for group B respectively (P>0.05). The time interval between the catheter implanting and the onset of peritonitis was (30±29) weeks and (29±24) weeks for group A and group B respectively (P>0.05). The risk of developing peritonitis in both groups was 26.97% within 1 year. Tunnel infection occurred in 2 patients and exit-site infections in 9 patients of two groups. The incidence of tunnel plus exit-site infections was 0.1 times/patient year. Incidence of tunnel infection and the exit-site infection for group A was lower than that of group B (0 vs 0.036 times/patient year and 0.06 times/patient year vs 0.11 times/patient year respectively). However, the difference was not significant (P>0.05). Mechanical complications of catheter (catheter migration, omentum wrapping, leakage of peritoneal dialysates, slip out of outer cuff), incidence of inguinal hernia and bellyache between two groups were not significantly different (P>0.05). There were 4 cases of catheter drawing in each group. Both two groups had the same 12-month technical survival rate as 92.73%. Of 17 dead cases, 7 were in group A and 10 in group B (P>0.05). The main death causes were cardiocerebral events (47.1%) and infections (23.5%). The 12-month survival rate was 86.34% for group A and 80.68% for group B(P>0.05). Conclusions There are no significant differences of infection, mechanical complications, technical survival rate and patients’ survival rate between two groups. The efficacy of swan-neck catheter is similar to Tenckhoff catheter in CAPD patients.
  • ZHANG Dong-liang;YIN Dao-xin;GUO Wang;LIN Ya-hui;LIU Wen-hu
    2008, 24(10): 690-694.
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    Objective To study the effect of long-term salmon calcitonin on bone mineral density (BMD), bone metabolism biochemical indicators and subjective score of bone pain in maintenance hemodialysis (MHD) patients with osteopenia. Methods Thirty-four MHD patients diagnosed as osteopenia by dual-energy X-ray absorptiometry (DXEA) were enrolled in this study. All the patients were treated with hypodermic injection of salmon calcitonin (50 U, thrice a week) for 12 months. The detecting parameters were as follows: BMD with DEXA in lumbar spine (L1-L4), femoral neck, troch, inter, and Ward’s triangle before and after the study; serum bone metabolism biochemical indicators before and 6 and 12 months after the study; subjective scores of bone pain before and 1, 6, and 12 months after the study. Results Thirty-two patients were followed-up successfully. As compared to BMD parameters before study, the total T-score (-1.98±2.20 vs 1.26±1.88, P=0.009) and total Z-score (-0.90±2.15 vs 0.08±2.05, P=0.002) of lumbar spine, the total T-score (-1.72±1.53 vs 1.06±1.58, P=0.016) and totle Z-score (-0.66±0.80 vs 0.08±1.08, P=0.029) of hip, the T-score of L3 (-2.02±2.51 vs 1.24±2.02, P=0.033), the Z-score of L2 (-0.44±1.82 vs 0.06±1.63, P=0.016), the Z-score of femoral troch (-0.65±1.11 vs 0.48±1.12, P=0.034) and the Z-score of inter (-0.58±0.94 vs 0.02±1.12, P=0.006) were increased significantly after study. But there were no significant differences in other examined regions and serum biochemical parameters. The subjective scores of bone pain were decreased rapidly for 41.7% after 1 month (P<0.01) and 76.6% after 6 months (P<0.01). The subjective score of bone pain after 12 months was similar to 6 months. The side effects of salmon calcitonin included nausea and vomitting in 5 cases (14.71%, 5/34), dizziness, blushing and flustered in 1 case respectively (3.13%,1/32). Conclusions Long-term hypodermic injection of salmon calcitonin can improve BMD and bone pain for MHD patients with osteopenia but has no significant effect on serum bone metabolism biochemical indicators. Salmon calcitonin is safe for MHD patients with seldom side effects, such as nausea and vomitting.
  • ZHAO Shi-li;YANG Qiong-qiong; MAO Hai-ping;CHEN Wei;HUANG Feng-xian;ZHENG Zhi-hua;CHEN Li-zhong;FEI Ji-guang;YU Xue-qing
    2008, 24(10): 695-700.
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    Objective To investigate the effects of hemodialysis (HD) and peritoneal dialysis (PD) on the complications and outcomes after renal transplantation. Methods Clinical data of 402 renal transplant recipients maintained on dialysis for more than 3 months were retrospectively studied and divided into 2 groups: HD group(n=303)and PD group(n=99). Among them, 345 recipients were followed up for an average of (30.2±15.2) months. The impact of HD and PD on the acute rejection, delayed graft function (DGF), infection, chronic rejection and the graft and patient survival rates were analyzed. Results The mean dialysis duration was significantly longer in PD group and the hepatitis B infection rate was significantly higher in HD group. There were no significant differences between the HD and PD groups in regarding to primary disease for end-stage renal disease, age, gender, blood pressure, hemoglobin, HLA match, hot and cold ischemia time, and hepatitis C virus infection. The incidence of DGF, acute and chronic rejection, and cytomegalovirus and other infections between HD and PD groups were not significantly different. However, the graft loss happened more frequently in hepatatis B patients than that in non hepatitis B patients (19.23% vs 8.86%, P=0.021), and the post-transplant infection ocurred less in non hepatits B patients with PD. The acute rejection episodes were higher in HD patients who received pretransplant dialysis for more than 12 months (P<0.05). The overall recipients survival rates of HD and PD groups were similar( 1-year: HD 94.34%, PD 91.25%; 5-year: HD 92.83%, PD 90%), and the same as the graft survival rates in HD and PD groups (1-year: HD 93.21%, PD 96.25%; 5-year: HD 87.17%, PD 91.25%). Conclusions The influences of PD and HD on the complications after renal transplantaton, 1-year and 5-year recipients and graft survival rates are similar, so both HD and PD can be chosen as the pretransplant dialysis modality. As the incidence of acute rejection increases with time in HD, it is better to shorten the time of pretransplant dialysis to decrease the complication.
  • LIAO Yun-hua;PAN Ling;CHEN Qing-yun;HUANG Li;HUO Dong-mei;SONG Ya-shan;CHEN Ying;TANG Xi-ping;MA Jian-hao;PENG Yu-huan;CHEN Qiang-wen;SU Fei-qun;ZHOU Cui-ping;LI Shui-lian
    2008, 24(10): 701-705.
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    Objective To investigate the prevalence and risk factors of chronic kidney disease (CKD) in the adult urban population of Hezhou Guangxi. Methods One thousand and two hundred urban residents (older than 18 years) from Hezhou Guangxi were randomly selected using a random sampling. All the residents were interviewed. Their morning spot urine were tested to determine albumin to creatinine ratio (abnormal:≥30 mg/g), and renal function [abnomal:eMDRD <60 ml·min-1·(1.73 m2)-1] was assessed. Morning spot urine dipstick of hematuria (abnormal: ≥l+) was confirmed by microscopy (abnormal: > 3 red blood cells/HP). The associations among demographic characteristics, health characteristics and indicators of kidney damage were examined. Results Eligible data of 1069 subjects were enrolled in the study. The prevalence of albuminuria was 7.5%, hematuria 4.8%, and reduced eGFR 3.6%. The prevalence of kidney disease was 14.4% and the recognition was 1.4%. Age(OR 1.022, 95%CI 1.008-1.035), gender (OR 2.249, 95%CI 1.502-3.367), diabetes mellitus (OR 7.422, 95%CI 3.985-13.825) and hypertension (OR 4.397, 95% CI 2.601-7.432) were independently associated with CKD. Conclusions The prevalence of chronic kidney disease is 14.4% and the recognition is 1.4% in adult urban population of Hezhou Guangxi. Independent risk factors associated with chronic kidney disease are age, gender, diabetes mellitus and hypertension which is similar to those in developed countries and domestic big cities.
  • LIU Yi;CHEN Li;ZHENG Chen-fei;XU Yu-lan;WANG Lv-ping;MEI Xiao-rong
    2008, 24(10): 706-710.
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    Objective To investigate the current status and changing patterns of hemodialysis in Wenzhou areas of China from 1999 to 2006. Methods Data of blood purification centres of 18 hospitals in Wenzhou areas from 1999 to 2006 were collected. The incidence, prevalence, mortality, the etiology and the relevant factors such as age, gender, dialysis ages, outcomes and causes of death in end stage renal disease(ESRD) patients on hemodialysis(HD) were analyzed retrospectively. Results The incident number and the number of patients increased annually while the mortality remained steady. The male patients outnumbered the female every year, but the male/female ratio was decreasing. The percentage of both young and oldly patients was increasing. The first cause was chronic glomerulonephritis, although the constituent ratio of glomerulonephritis decreased year by year. The constituent ratio of diabetic nephropathy and hypertensive nephropathy increased. The constituent ratio of dialysis age 1-2 years group decreased, ≤1 year, 2-3 years, 3-4 years groups were relatively steady, and 4-5 years, 5-10 years, >10 years groups increased. The number of patients receiving renal transplantation and transferring to peritoneal dialysis increased annually. The leading cause of death was cardiovascular incidence (19.9%), followed by cerebrovascular disorder(10.8%), systemic failure(10.8%), hemorrhagic diseases(4.7%) and infectious diseases(4.3%). The constituent ratio of cardiovascular incidence and cerebrovascular disorder were relatively steady. The constituent ratio of hemorrhagic diseases and systemic failure showed great fluctuation. The constituent ratio of infectious diseases and malnutrition was decreasing. Conclusions In Wenzhou area from 1999 to 2006, the patients number has been increasing annually. The onset age of HD is 30-70 years old, and proves a younger tendency and older tendency. The leading cause is chronic glomerulonephritis. The constituent ratio of diabetic nephropathy and hypertensive nephropathy rises year by year. The long-term survival rate of HD patients is improved. The leading cause of death is cardiovascular accident.
  • 基础研究

  • U Jun;YANG Xiao;ZHANG Yun-fang;ZHANG Rui;DONG Xiu-qing;FAN Jin-jin;LIU Mei;YU Xue-qing
    2008, 24(10): 711-717.
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    Objective To investigate the effects of angiotensin Ⅱ(AngⅡ) on the expression of TLR4 and its role in lipopolysaccharide (LPS)-induced NF-κB activation and CD40 expression in rat peritoneal mesothelial cells (RPMCs). Methods RPMCs were harvested from Sprague-Dawley rat peritoneal cavity and maintained under defined in vitro condition. The cells were treated with AngⅡ at different concentrations (10-9, 10-8, 10-7, 10-6 mol/L) and exposed to AngⅡ (10-7 mol/L) for different times (1, 2, 4, 8, 12, 24, 48 h for mRNA and 6, 12, 24, 36, 48 h for protein, respectively). Meanwhile, the influence of AT1 receptor antagonist (AT1R, losartan, 10-5 mol/L) and AT2 receptor blocker (AT2R, PD123177, 10-5 mol/L) on the TLR4 induced by AngⅡ was observed. After synchronization for 24 hours, the cells were randomly assigned to four groups: the control group, the AngⅡ (10-7 mol/L) group, the LPS (1 mg/L) group, the AngⅡ (10-7 mol/L) plus LPS (1 mg/L) group, which were used to investigate the effects of AngⅡ on the NF-κB activation and CD40 expression induced by LPS. The mRNA expression of TLR4 and CD40 was measured by RT-PCR and the protein abundance of TLR4, NF-κB p65, phospho-p65, IκBα and phospho-IκBα were analyzed by Western blot. Immunofluorescence was performed to determine the subcellular localization of p65 subunit of NF-κB. Results (1) Treatment of RPMCs with AngⅡ resulted in a concentration-dependent increase in the expression of TLR4. AngⅡ at 10-9, 10-8, 10-7 and 10-6 mol/L increased TLR4 mRNA expression by 70.5%, 89.5%, 102.9%, and 121.9%, respectively and protein expression by 12.1%, 27.7%, 51.2%, and 41.6%, respectively (P<0.01). Treatment of RPMCs with 10-7 mol/L AngⅡ resulted in a time-dependent increase in the expression of TLR4, with the peak of mRNA expression at 8 and 12 h (P<0.01) and the protein expression at 12 and 24 h (P<0.01). (2) Losartan antagonized AngⅡ-stimulated expression of TLR4 by 33.5% (P<0.05), PD123177 had no such effect (P>0.05). (3) Treatment of RPMCs with LPS (1 mg/L) for 60 min significantly increased the ratio of phospho-IκBα to IκBα by 362.6% (P<0.01) , phospho-p65 to p65 by 67.4% (P<0.05), and LPS (1 mg/L) for 4 h significantly increased the expression of CD40 mRNA by 299.9% (P<0.01) compared to the control group. In comparison to the LPS (1 mg/L) group, preincubation of RPMCs with AngⅡ (10-7 mol/L) for 24 h then treated with LPS (1 mg/L) for 60 min significantly increased the ratio of phospho-IκBα to IκBα by 49.1% (P<0.01), phospho-p65 to p65 by 29.3%(P<0.05), and LPS (1 mg/L) for 4 h significantly increased the expression of CD40 mRNA by 56.8%(P<0.01). (4) The p65 subunit of NF-κB was dominantly distributed in the cytoplasm in the control and AngⅡ group. Following exposure to LPS for 60 min, p65 subunit labeling was upregulated and translocated into the nuclei. A significantly increased nuclear staining of p65 in cells treated with AngⅡ plus LPS were observed. Conclusions AngⅡ induces the expression of TLR4 in dose- and time-dependent manner in RPMCs, resulting in enhanced NF-κB signaling and induction of CD40 expression. Locally produced AngⅡ in the peritoneum may play an amplified role in LPS-induced peritoneal inflammation.
  • LIU Ying-li;XIN Jing;GU Yong;YANG Hai-chun;MA Ji;Taiji Matsusaka;Iekuni Ichikawa;LIN Shan-yan
    2008, 24(10): 718-724.
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    Objective To explore the glomerular change of renin-angiotensin system (RAS) expression in AT1aR gene knockout mice and its effects on extracellular matrix (ECM)remodeling under diabetic condition. Methods AT1aR knockout mice were generated previously. Hyperglycemia was induced by peritoneal injection of streptozotocin in AT1aR knockout mice and wild type mice. Normal AT1aR knockout mice and wild type mice were used as control group. Twelve weeks later, kidneys were harvested and frozen quickly in dry ice-acetone. Glomeruli were collected by laser capture microdissection and total RNA was extracted. mRNA expression of AT1aR, AT1bR, AT2R, angiotensinogen, ACE, renin, and CYP11B2 was assessed by real-time PCR. ECM accumulation was evaluated by PAS staining. Protein levels of transforming growth factor β1(TGF-β1), type 1 plasminogen activator inhibitor(PAI-1), monocyte chemotactic protein 1(MCP-1) and renin were semi-quantitated by immunostaining. Results Compared to the wild type, mRNA expression of AT1bR, angiotensinogen, renin, CYP11B2 within glomeruli was upregulated significantly in AT1aR knockout mice (P<0.05), but no change of ACE expression was found in these two groups. AT2R protein was poorly detected in AT1aR knockout glomeruli and downregulated in wild type glomeruli. ECM accumulation was significantly increased associated with the parallel increase in TGF-β1, PAI-1, MCP-1 and renin within glomeruli(P<0.05). Conclusions AT1aR gene knockout cannot improve ECM deposition in diabetic nephropathy. The compensate change of RAS components may be involved in this scenario: upregulation of AT1bR, downregulation of AT2R. CYP11B2 and renin may function in a novel pathway.
  • LIU Hua;LI Hang;TAO Jian-ling;WEN Yu-bing;LI Xue-wang
    2008, 24(10): 725-729.
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    Objective To observe the impact of IL-1β on the expression of lectin-like oxidized LDL receptor 1(LOX-1) and ATP-binding cassette transporter A1(ABCA1) in human mesangial cell line (HMCL), and its association with cholesterol homeostasis of HMCL. Methods Levels of LOX-1 and ABCA1 of HMCL induced by IL-1β were examined by using real-time PCR and Western blot. Results IL-1β up-regulated LOX-1 mRNA and protein expression. Treated with 5 μg/L IL-1β, the levels of LOX-1 mRNA and protein reached the peak after 6 h and 24 h of stimulation and were 6.87 folds and 1.88 folds of control rspectively. The expression of ABCA1 mRNA and protein of lipid-loaded HMCL was down-regulated by IL-1β. Stimulated with 5 μg/L IL-1β, the expression of ABCA1 mRNA and protein decreased to the lowest level, 19.0% and 50.62% of the baseline respectively. Conclusions The expression of LOX-1 can be up-regulated while the expression of ABCA1 can be decreased by the stimulation of IL-1β. IL-1β can enhance dyslipidemia and influence the balance of cholesterol homeostasis of HMCL.
  • LI Ying-juan;DUAN Shao-bin;ZHOU Xiao-rong;WANG Yu-hui;LI Jun;PENG You-ming;LIU Fu-you
    2008, 24(10): 730-735.
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    Objective To evaluate the nephrotoxicity induced by radiographic contrast media with different osmolality in rats with hypercholesterolemia, and to explore the protective effect of pentoxifylline. Methods Forty-eight healthy SD male rats were randomly divided into normal dietary group (NN, n=8) and high cholesterol supplemented dietary group (H, 4% cholesterol and 1% cholic acid, n=40). At the end of 8th week, the rats with high cholesterol diet were randomly divided into five subgroups (n=8, respectively): high cholesterol diet group(HN), high cholesterol plus iso-osmolar contrast media (iodixanol, IOCM) group (HI), high cholesterol plus low-osmolar contrast media (iohexle, LOCM) group(HL), high cholesterol diet plus high-osmolar contrast media (diatrizoate, HOCM) group (HH) and high cholesterol plus HOCM plus pentoxifylline group (HHP). Forty-eight hours after contrast media injection, the rats were executed and blood samples were prepared to determine total cholesterol, triglyceride, serum creatinine, creatinine clearance(Ccr), fractional excretion of sodium and potassium(FeNa, FeK), and angtensionⅡ(AngⅡ) levels. The renal injury was assessed by HE staining and TUNEL staining, respectively. The expression of NF-κB protein in the renal tissue was detected by using immunohistochemical method. Results An increase of cholesterol was observed in all the rats with high cholesterol diet. Scr, FeNa%, FeK% and AngⅡlevels of rats in HH group were obviously higher than those in HL and HI groups respectively. Ccr in HH group[(0.11±0.02) ml·min-1·(100 g)-1] was significantly lower than that in HHP group [(0.43±0.03) ml·min-1·(100 g)-1], HL group [(0.25±0.02) ml·min-1·(100 g)-1] or HI group [(0.27±0.03) ml·min-1·(100 g)-1] (P<0.05). TUNEL staining showed that the percentage of apoptotic cells in HH group [(89.60±6.40)%] was higher than that of the other groups [NN (2.40±0.77)%, HN (5.60±1.08)%, HHP (8.91±1.44)%, HL (63.34±11.97)% and HI (61.50±9.40)%]. Immunohistochemistry staining showed that the average gray value of NF-κB positive cells in HH group decreased (P<0.05). There were no significant differences of all indices between HL and HI groups (P>0.05). Conclusions Contrast media can cause kidney injuries in the rats with hypercholesterolemia. PTX can protect the renal tissue from nephrotoxicity induced by HOCM in hypercholesterolemia.
  • LI Jing;LI Hang;WEN Yu-bing;LI Xue-wang
    2008, 24(10): 736-742.
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    Objective To investigate the role of LPL in enhancing VLDL uptake in mesangial cells and modulating VLDL-mesangial interaction. Methods Human wild type LPL (LPLwt), catalytically inactive LPL (LPL194) or control alkaline phosphatase (AP) were expressed in human mesangial cell line (HMCL) via adenoviral vectors. The expression of LPL mRNA and protein was detected by RT-PCR and immunochemistry staining, respectively. LPL activity was assayed by radioisotope labeled liposome substrate. Cellular lipid deposition was visualized by oil red O staining and analyzed quantitatively by standard enzymatic procedures. Effect of LPL on HMCL proliferation was evaluated by colorimetric assay using MTT. MCP-1 mRNA and protein levels in treated HMCLs were determined by real-time quantitative RT-PCR and enzyme-linked immunosorbent assay respectively. For adhesion study, HMCLs were treated with VLDL for six hours, followed by one-hour incubation with Tamm-Horsfall protein-1 (THP-1) cells. Results Compared with HMCLs transfected by Ad-AP, the lever of cellular triglyceride content was sharply increased in Ad-LPLwt transfected HMCLs [(109.11±5.01) mg/g protein vs (23.98±3.23) mg/g protein, P<0.01] and was slightly increased in Ad-LPL194 transfected HMCLs[(36.33±2.64) mg/g protein vs (23.98±3.23) mg/g protein, P<0.05]. LPLwt amplified VLDL-driven mesangial cells proliferation. Compared to the HMCL-Ad-AP, MCP-1 mRNA and protein expression increasd by 39% (P<0.05) and 171% (P<0.01) in HMCL-Ad-LPLwt, and the amount of THP-1 cells adhering to HMCL-Ad-LPLwt was increased by 1.69-fold (P<0.05), without significant difference between HMCL-Ad-LPL194 and HMCL-Ad-AP. Conclusions Overexpression of either active or inactive LPL in HMCLs accelerates VLDL-induced triglyceride accumulation, and enzymolysis action of LPL may be the major factor in this process. Active LPL significantly amplifies VLDL-induced proliferative effect on mesangial cells and enhances monocyte adhesion to mesangial cells through up-regulation of MCP-1. Hence, LPL may be an important contribution to initiation and progression of renal injury mediated by triglyceride-rich lipoproteins.
  • PENG Wei;LIU Zheng-rong;REN Hao;ZHOU Zhan-mei;TIAN Jian-wei
    2008, 24(10): 743-750.
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    Objective To observe whether bone marrow mesenchymal stem cells (MSCs) can promote the repair of IgA nephropathy and to explore its possible mechanism. Methods Sprague-Dawley rats were randomly divided into three groups which were MSCs injection group, normal saline(NS) infusion group and healthy control group. IgA nephropathy model was established by the improving method with BSA+SEB+CCl4 in former two groups. MSCs of SD rats were continuously cultured in vitro and identified with specific surface antigens by flow cytometry and osteogenic and adipogenic differentiation. MSCs were labeled with bromodeoxyuridine (BrdU) in vitro before transplanted. At 1st and 4th week after MSCs injection, the changes of body weight, urine protein, renal function, histopathology and IgA immunofluorescence were observed. MCP-1, TGF-β1 in urine were detected by ELISA. The expression of MCP-1, TGF-β1 in kidney were examined by RT-PCR. The cytokines and BrdU labeled MSCs were detected by immunohistochemistry to observe the disposition in kidney. Results At the end of the first week of MSCs transplantation, MSCs group urine protein (36.86±4.78) mg/24 h, serum creatinine (53.50±6.28) μmol/L, and the NS group urine protein (66.98±5.86) mg/24 h, serum creatinine (82.50±8.36) μmol/L, the differences between two groups were significant(P<0.05). At the same time, the content of MCP-1, TGF-β1 in urine and expression in renal tissue of MSCs group were obviously less than those of NS group(P<0.05). At the end of the 4th week, the body weight, histopathology, IgA immunofluorescence of MSCs group were remarkably improved as compared with those of NS group. The content of MCP-1, TGF-β1 in urine and expression in renal tissue, and renal pathological change in MSCs group had no significant differences as compared with those of healthy control group. As the time passed, the disposition of BrdU-labeled MSCs in kidney was taper. Conclusions MSCs injection contributes to renal repair in rat IgA nephropathy. The mechanism may partly depend on adjusting the excretion of cytokines in renal microenvironment and/or other functions rather than completely depend on their differentiation to renal cells.
  • LI Yue-hong;George Seki;WANG Mei
    2008, 24(10): 751-758.
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    Objective To clarify the signaling mechanisms underlying angiotensin II biphasic regulation of renal proximal Na+-HCO3- transport. Methods Different concentration AngⅡ to the responses of Na+-HCO3- cotransporter(NBC) activity in isolated proximal tubules, with or without ATR, MAPK, cPLA2α, P450 blockade was compared in wild-type and AngⅡ type 1a receptor (AT1aR)-deficient mice. The phospholipase of ERK was examined by Western blotting. AT1aR mRNA was examined by RT-PCR from kidney proximal tubules. Results (1)In isolated wild-type mouse, renal proximal tubules showed biphasic effects of AngⅡ on NBC activity. Low concentration AngⅡ (10-10 mol/L) increased NBC activity, but high concentration AngⅡ (10-6 mol/L) decreased NBC activity. Olmesartan (AT1 antagonist) blocked both stimulatory and inhibitory effects of AngⅡ on NBC activity, but PD98059 (mitogen-activated protein kinase inhibitor) blocked only the stimulatory effect of low concentration AngⅡ(10-10 mol/L). (2)In AT1aR-deficient mice, only the stimulatory effect by high concentration of AngⅡ (10-6 mol/L) was observed, which was blocked by olmesartan and PD98059. (3)In wild-type mice, pharmacological blockade of cPLA2 or P450 converted the inhibition effect by high concentration AngⅡ (10-6 mol/L) to the stimulation, which was blocked by olmesartan and PD98059. These results indicated that the extracellular signal-regulated kinase (ERK) activation via AT1 mediated only the stimulatory effect of AngⅡ, while the cPLA2α/P450 activation via AT1 mediated the inhibitory effect of AngⅡ independently of ERK. The analysis of ERK phosphorylation by AngⅡ also supported a view that the cPLA2α/P450 pathway worked to suppress the ERK activation. Conclusions AngⅡ activates ERK and cPLA2α with different concentration dependency via AT1. The balance between ERK and cPLA2α activities determines the final responses to AngⅡ in intact proximal tubules.